Metering doses of sample liquids

ABSTRACT

A device and method of metering and mixing a dose of a sample liquid with a diluent liquid includes introducing a sample liquid into a channel defined in a housing. The housing defines a pocket open to the channel and sized to both collect a metered dose of the sample liquid, and to retain the collected dose by capillary force when the channel is emptied. The sample liquid is then removed from the channel under conditions that enable retention of the collected, metered dose of the sample liquid in the pocket. Following a cleaning step, a volume of diluent liquid is introduced into the channel to induce diffusion and mixing of the diluent liquid with the dose of sample liquid to form a mixture.

CROSS -REFERENCE TO RELATED APPLICATIONS

This application is a continuation (and claims the benefit of priorityunder 35 U.S.C. 120) of U.S. patent application Ser. No. 10/911,845,filed Aug. 5, 2004. U.S. patent application Ser. No. 10/911,845 claimsthe benefit of prior U.S. Provisional Application Ser. No. 60/544,897,filed Feb. 17, 2004, and No. 60/547,958, filed Feb. 27, 2004. Thedisclosure of the prior applications are considered part of (and areincorporated by reference in their entirety in) the disclosure of thisapplication.

TECHNICAL FIELD

This invention relates to metering and mixing doses of a sample liquidwith a diluent liquid within a liquid transfer device, such as with apipette.

BACKGROUND

The science and economics of drug discovery has changed withdevelopments in the areas of genomics, combinatorial chemistry andhigh-throughput screening. The number of targets has increased as aresult of genomics while the number of small molecule compounds(samples) has dramatically increased as a result of combinatorialchemistry. This increase in targets and compounds has an exponentialeffect on the number of tests that need to be performed to increase thelikelihood of finding a new chemical entity using high-throughputscreening. Microliter amounts of target and sample must suffice for manyscreening assays, putting pressure on the automation industry to providenew tools to increase throughput, efficiency, and reduce R&D costs.Conventional R&D screening efforts use multiple variations of pipettingto move aliquots of the concentrated liquid sample from storagereceptacles, to working receptacles, to dilution receptacles and finallyto assay receptacles. This “reformatting” process, or “sample prep.”adds complexity to the overall process, wastes valuable sample ortarget, and increases time and assay cost.

Disposable pipette tips and non-disposable, cleanable pipetting devicesare commonly used for proportioning liquids. Pipette tips and pipettingdevices include an input aperture at one end and a placement aperture atthe other end for attachment to the pipetting device. The pipettingdevice often encompasses a piston-cylinder positive displacementmechanism. The pipette tip attaches to the pipetting device through avariety of mechanical connection schemes. A column of air connects thepiston-cylinder mechanism to the pipette tip through a fluidicinterface. Liquid is aspirated into the pipette tip when the pipettetip's input aperture is submerged in liquid while the piston-cylindermechanism draws in. The air column and aspirated liquid draw into thepipette tip via a proportioned amount. The liquid is dispensed from thetip by reversing the direction of the piston-cylinder mechanism. Theamount of liquid that may be aspirated and dispensed is limited by anumber of factors including but not limited to: pipette tip material,pipette tip surface finish, input aperture capillary forces, liquidsurface energy, and piston-cylinder mechanism limitations.

Tubes, capillary channels, and plate surfaces make-up categories ofdevices that are used in many market applications that involve thetransfer of fluids. In the drug discovery market, new developments inthe area of “chip” based systems involve capillary channels to movefluids through a myriad of systemic processes. In the diagnostic market,tubes and pipetting devices are used to perform a number of liquidtests, all burdened by the limited amount of source liquid vs. thenumber of tests that are desired to be run against those source liquids.

SUMMARY

In general, in one aspect the invention provides a method for meteringand mixing a dose of a sample liquid with a diluent liquid and includesintroducing a sample liquid into a channel defined in a housing, thehousing defining a pocket open to the channel and sized to collect ametered dose of the sample liquid, and to retain the collected dose bycapillary force when the channel is emptied; removing the sample liquidfrom the channel under conditions that enable retention of the collectedmetered dose of the sample liquid in the pocket; and then introducing avolume of diluent liquid into the channel to induce diffusion and mixingof the diluent liquid to form a mixture.

Some embodiments include cleaning the channel following the removal ofthe sample liquid from the channel and prior to the introduction ofdiluent liquid into the channel. The cleaning step includes introducinga cleaning liquid into the channel below the pocket; and then removingthe cleaning liquid from the channel to flush any residual sample liquidfrom surfaces of the channel below the pocket.

In some cases the housing includes a tube defining the channel. In thesecases, the tube can have an open lower end through which the sampleliquid is introduced by drawing the liquid into the tube. The channelcan be narrow and/or the pocket can be disposed on a portion of thechannel wider than the channel at the open end of the tube. The pocketcan include an upwardly extending notch defined in an interior wall ofthe tube. The surface of the tube can define a lower extent of thepocket that is substantially perpendicular to a longitudinal axis of thetube. In some embodiments, the pocket can be elongated and parallel to alongitudinal axis of the tube.

In some cases, the housing includes a laminated plate that defines theliquid channel, the pocket and an input orifice in fluid contact withthe channel. In these cases, the sample liquid can be introduced andremoved from the channel pneumatically.

In some embodiments, the method further includes dispensing a meteredvolume of the mixture into a destination well. The mixture can bedispensed by pneumatically propelling the mixture from the housing.Also, the mixture can be propelled from the housing by pressurized gas.

In some cases, the volume of diluent liquid introduced into the channelis in the range of between about 1 nanoliter and 1 milliliter.

In some embodiments, the housing defines a plurality of said pocketsspaced apart from one another.

Implementations may include one or more of the following features. Forexample, the pocket can be formed from a method selected from the groupconsisting of molding, machining, welding, and coating or other suitablemeans for producing a capillary retainment feature. The pocket can beformed of a material secured to a material forming an inner surface ofthe housing. The pocket can be defined in a protrusion extending intothe channel.

In another aspect, the invention provides a method of metering andmixing a dose of a sample liquid with a diluent liquid and includesdrawing a sample liquid into a pipette defining an internal cavity andhaving an interior wall defining a pocket sized to collect a metereddose of the sample liquid; followed by expelling the sample liquid fromthe pipette under conditions that enable retaining the collected,metered dose of the sample in the pocket by capillary force; and thendrawing a volume of the diluent liquid into the pipette a sufficientdistance to contact the retained dose of sample liquid, to inducediffusion and mixing of the diluent liquid with the dose of sampleliquid.

Some embodiments include cleaning the pipette after expelling the sampleliquid from the pipette and prior to drawing the diluent liquid into thepipette. The cleaning step includes drawing a cleaning liquid into thepipette below the pocket; and then expelling the cleaning liquid fromthe pipette to flush any residual sample liquid from surfaces of theinterior wall below the pocket.

In some embodiments, the method further includes dispensing a meteredvolume of the mixture into a destination well. The mixture can bedispensed by pneumatically propelling the mixture from the pipette. Insome cases, the pipette further defines a capillary hole between anouter surface of the pipette and the internal cavity. In these cases,the mixture can be propelled from the pipette by forcing a pressurizedgas into the internal cavity through the capillary hole.

In some cases, the internal cavity is narrower at a lower open end ofthe pipette than in an upper section of the pipette. In these cases, thepocket can be disposed in a portion of the internal cavity wider thanthe internal cavity at the open end of the pipette.

In some embodiments, a surface of the pipette defining a lower extent ofthe pocket is substantially perpendicular to a longitudinal axis of thepipette.

In some cases, the pocket is elongated and parallel to a longitudinalaxis of the pipette.

In some embodiments, the volume of diluent liquid introduced into theinternal cavity is in the range of between about 1 nanoliter and about500 microliters.

In some cases, the pipette can define a plurality of said pockets spacedapart from one another, either parallel to the axis of the pipette orradially.

Implementations may include one or more of the following features. Forexample, the pipette can be formed from a synthetic resin. The pocketcan be formed from a method selected from the group consisting ofmolding, machining, welding and coating or other suitable means forproducing a capillary retainment feature. Also, the pocket can bedefined as a protrusion extending into the internal cavity.

In yet another aspect, the invention provides a method of metering andmixing a plurality of doses of a sample liquid with a diluent liquid andincludes providing an array of pipettes, each pipette defining aninternal cavity and having an interior wall defining a pocket sized tocollect a metered dose of a sample liquid; drawing the sample liquidinto the pipettes; then expelling the sample liquid from the pipettesunder conditions that enable retaining the collected, metered doses ofthe sample in pocket by capillary force; and then drawing a diluentliquid into the pipettes a sufficient distance to contact the retaineddoses of sample liquid, to induce diffusion and mixing of the diluentliquid with doses of the sample liquid.

Some embodiments include cleaning the pipettes after expelling thesample liquid from the pipettes and prior to drawing the diluent liquidinto the pipettes. The cleaning step includes drawing a cleaning liquidinto the pipettes below the pockets; and then expelling the cleaningliquid from the pipettes to flush any residual sample liquid fromsurfaces of the interior wall below the pocket.

In some embodiments, the method includes dispensing from each pipette ametered volume of the mixture into a destination well. Dispensing themetered volume can include pneumatically propelling the mixture from thepipettes. Also, each pipette can define a capillary hole between anouter surface of the pipette and the internal cavity, and the mixturecan be propelled from the pipette by forcing a pressurized gas into theinternal cavity through the capillary hole.

In some embodiments, the internal cavity is narrower at a lower open endof the pipette than in an upper section of the pipette. In theseembodiments, the pocket can be disposed in a portion of the internalcavity wider than the internal cavity at the open end of the pipette.

In some cases, the pocket includes an upwardly extending notch definedin an interior wall of the pipette.

In some embodiments, a surface of the pipette defining a lower extent ofthe pocket is substantially perpendicular to a longitudinal axis of thepipette.

In some cases, the pocket is elongated and parallel to a longitudinalaxis of the pipette.

In some embodiments, the volume of diluent liquid introduced into theinternal cavity is in the range of between about 1 nanoliter and about500 microliters.

In some cases, the pipette defines a plurality of said pockets spacedapart form one another, either parallel to the axis of the pipette orradially.

In some embodiments, the method includes dispensing a metered volume ofthe mixture in an array of liquid-receiving units. In these embodiments,the array of pipettes can be aligned directly above the array of liquidreceiving units. The array of liquid receiving units can include amulti-well container. The multi-well container can be selected from thegroup consisting of a 96-well microtiter plate, a 384-well microtiterplate, and a 1536-well microtiter plate.

Implementations may include one or more of the following features. Forexample, the method can include dispensing a metered volume of themixture onto a slide. Also, the method can include dispensing a meteredvolume of the mixture onto an electronic assay reading device.

In one aspect the invention provides a pipette including an elongatedbody having an outer surface and defining an internal cavity open at alower end of the body; the body defining an opening in an upper portionof the body, through which air can be drawn from the cavity to drawfluids into the cavity through the lower end of the body; wherein thebody has an interior wall defining a pocket open to the internal cavity,the pocket sized to collect and retain a metered dose of a liquid drawninto the cavity as the cavity is otherwise evacuated.

In some embodiments of the device, multiple molded internal or externalpockets are present to provide a variable amount of final dispensedliquid volume. In some embodiments of the device, the internal orexternal pockets may be created by means other than molding, such asmachined pockets, welded pockets, coated pockets, etc. In someembodiments of the device, the pockets may be secondary parts (such asovermolded or insert molded parts) that are attached to the liquidcarrying device.

In some cases, the body further defines a capillary hole extending fromthe outer surface to the internal cavity.

In some cases, the pocket is disposed in a portion of the internalcavity wider than the cavity at the open end of the body.

In some embodiments, the pocket includes an upwardly extending notchdefined in the interior wall of the body.

In some cases, the surface of the pipette defining a lower extent of thepocket is substantially perpendicular to a longitudinal axis of thebody.

Implementations may include one or more of the following features. Forexample, the body can be formed from a synthetic resin. The body candefine a plurality of said pockets spaced apart from one another, eitherparallel to the axis of the pipette or radially. Also, the pocket can bedefined in a protrusion extending into the internal cavity.

Implementations of any of the foregoing may include one or more of thefollowing features. The pocket is preferably sized to collect a metereddose of sample liquid between about 1 nanoliter and about 10 microlitersin volume. More preferably, the pocket can be sized to collect a metereddose of sample liquid between about 5 nanoliters and about 10microliters in volume. The pocket dimensions preferably range frombetween about 0.001 and 0.04 inch (0.025 and 1.02 millimeters) wide andbetween about 0.001 and 0.100 inch (0.025 and 2.54 millimeters) deep,more preferably, between about 0.008 and 0.020 inch (0.204 and 0.51millimeters) wide and between about 0.008 and 0.04 inch (0.204 and 1.02millimeters) deep. The length of the pocket preferably ranges frombetween about 0.01 and 1 inch (0.25 and 25 millimeters) long. A definingsubset of features includes very small pocket wall radii, preferablyranging from between about 0.0005 and about 0.005 inch (0.013 and 0.127millimeters) and a textured surface finish ranging from 2 microns to 256microns. The diluent liquid can be moved reciprocally across the pocketmultiple times, to induce mixing with the dose of sample liquid.

The devices disclosed herein are designed to capture a repeatable volumeof source liquid by use of surface tension, geometry, or chemicaladhesion. These devices may include tubes, plates, wells or reservoirs,capillary channels, disposable and non-disposable pipette tips,instruments whose main function is to aspirate and dispense liquids, andinstruments whose main function is to move liquids through capillarychannels, tubes, and pipette tips or across plates. All devices in thisinvention are intended to include the concept of metering a fixed orvariable amount of source liquid, captured in the above mentionedpocket, followed by the dilution and mixing by a second liquid. Thismixture may either be dispensed in full or in part, stored in the tube,pipette tip or channel, or moved through capillary channels or plates toanother location.

This device can be made from materials common to the LifeSciences orMedical Diagnostics industry. The most common material for a disposablepipette tip is polypropylene, which may be filled with pigments, carbon,or other utility or function enhancing additives. Disposable pipettetips may also be made from other common molded plastics such aspolypropylene, polystyrene, polycarbonate or others. Non-disposablepipette tips are often made from various grades of stainless steel,glass or other metals or plastics, and are often coated with hydrophobiccoatings such as Teflon™ or Parylene™.

The details of one or more embodiments of the invention are set forth inthe accompanying drawings and the description below. Other features,objects, and advantages of the invention will be apparent from thedescription and drawings, and from the claims.

DESCRIPTION OF DRAWINGS

FIG. 1 is a side view of a pipette tip device.

FIG. 1A is a cross-sectional view, taken along line 1A-1A in FIG. 1.

FIG. 2 is a perspective view of an array of pipette tips aligned over areceptacle plate.

FIG. 2A is a sectional view of an array of pipette tips attached to apipette adaptor array and a pipettor.

FIG. 3 is sectional view of a single pipette tip with the tip inputaperture submerged in the source liquid stored in a source receptacleplate.

FIG. 4 is a sectional view of a single pipette tip with the sourceliquid aspirated into the input aperture and in contact with theinternal molded pockets.

FIG. 5 is a sectional view of a single pipette tip with the sourceliquid dispensed back into the source receptacle plate.

FIG. 6 is a sectional view of a single pipette tip showing the sourceliquid that remains inside the internal molded pipette tip pockets.

FIG. 6A is an enlarged sectional view of a single pipette tip showingthe source liquid that remains inside one internal molded pocket.

FIG. 7 is a sectional view of a single pipette tip with the pipette tipaligned over a system liquid receptacle device.

FIG. 8 is a sectional view of a single pipette tip with the systemliquid aspirated into the input aperture.

FIG. 9 is a sectional view of a single pipette tip with the aspiratedsystem liquid located in between the lower and upper internal moldedpocket.

FIG. 10 is a sectional view of a single pipette tip showing the finaldestinations of the system liquid that has mixed with source liquid fromthe two internal molded pockets.

FIG. 11 is a side view of a single pipette tip showing a through-wallcapillary hole.

FIG. 11A is a cross-sectional view, taken along line 11A-11A in FIG. 11.

FIG. 12 is a side view of a single pipette tip.

FIG. 12A is a cross-section view, taken along line 12A-12A in FIG. 12,showing another internal molded element that extends from the insidesurface into the pipette tip.

FIG. 13 is an isometric view of a single pipette tip.

FIG. 13A is a cross-sectional view of the pipette tip illustrated inFIG. 13, showing another internal molded element that includes themetering geometry and surface finishes and that extends from the insidesurface into the pipette tip.

FIG. 13B is an enlarged detail of the cross-sectional view of thepipette tip shown in FIG. 13A.

FIG. 14 is an isometric sectional view of a tube that contains one ormore internal elements that function to meter the source liquid viageometry and surface finish.

FIG. 14A is a cross-sectional side view of the tube illustrated in FIG.14.

FIG. 15 is an isometric sectional view of a capillary channel residingon a “chip” that contains one or more internal elements that functionsto meter the source liquid via its geometry and surface finishes. Onceon the chip, samples are manipulated through the channels of the chip toperform the steps required for mixing, incubation, reaction, separation,and detection. Movement through the channels is controlled using acombination of pressure and/or voltage, as known in the art.

FIG. 15A is a cross-sectional side view of the capillary chipillustrated in FIG. 15.

FIG. 16 is a sectional view of a plate that contains one or moreinternal elements that function to meter the source liquid via theirgeometry and surface finish.

FIG. 17 is a cross-sectional view of a pipette tip that includes aradial ledge that forms a capillary retention feature, and FIG. 17A isan enlarged view of area 17A in FIG. 17.

FIG. 18 is a cross-sectional view of a pipette tip that includes aseries of radial ledges that form capillary retention features and FIG.18A is an enlarged view of area 18A in FIG. 18.

Like reference symbols in the various drawings indicate like elements.All pipette tip designations are intended to include disposable,non-disposable and tube-based liquid transportation devices.

DETAILED DESCRIPTION

FIGS. 1-1A show a first pipette tip device 10. Referring to FIG. 1A, thepipette tip 10 has an input aperture 11 and a placement aperture 12. Theinternal molded pockets 13 function to capture and hold a fixed amountof source liquid.

FIG. 2 is a perspective view of an array of pipette tips 10 that areattached to a pipette adaptor array 16. The array of pipette tips 10 arealigned over a microtiter plate 14 which can include different arraydensities such as 96, 384, and 1536. Each pipette tip 10 is aligned withan individual well 15.

FIG. 2 a is a sectional view of an array of pipette tips 10 that areattached to the pipette adaptor array 16 which attaches to the pipettor39. The pipettor 39 is typically constructed of an array of pipettorcylinders 40 and pipettor pistons 41 used for positive displacementactuation.

In illustrating the operation of the pipette tip device 10, FIG. 3through FIG. 10 are sequential.

In FIG. 3, microtiter plate 14 includes source liquid 17 in eachindividual well 15. The pipette tip 10 input aperture 11 is submergedinto the source liquid 17.

In FIG. 4, the pipettor 39, via the pipette adaptor array 16, aspiratessource liquid 17 into pipette tip 10 through input aperture 11. Thesource liquid 17 is aspirated to the same level or higher than theinternal molded pocket or pockets 13.

In FIG. 5, the pipettor 39, via the pipette adaptor array 16, dispensesthe source liquid 17 back out of pipette tip 10 through input aperture11. Further motion of the pipette actuation device will begin to pushair 18 out of the input aperture 11.

In FIG. 6, the microtiter plate 14 with the source liquid 17 is removed.The internal molded pockets have each captured and retained a fixedamount of source liquid 17.

In FIG. 6 a, an enlarged view of the internal molded pocket 13 filledwith source liquid 17 is presented.

In FIG. 7, a second microtiter plate 14 with a diluting system liquid 20in each individual well 15 is brought into contact with the pipette tip10 such that the input aperture 11 is submerged.

In FIG. 8, the pipettor 39, via the pipette adaptor array 16, aspiratesa fixed amount of diluting system liquid 20 into the pipette tip 10through input aperture 11.

In FIG. 9, the diluting system liquid microtiter plate 14 is removed.The pipettor 39, via the pipette adaptor array 16, aspirates the fixedvolume of diluting system liquid 20 higher into the pipette tip 10. Asthe system liquid 20 passes by the internal molded pockets 13, thesource liquid 17 that was retained in the pockets 13 is acquired by thediluting system liquid 20 to become mixture 21. The pipettor 39, via thepipette adaptor array 16, mixes the system liquid 20 up and down once ormultiple times to create the mixture 21.

In FIG. 10, the pipettor 39, via the pipette adaptor array 16, dispensesthe mixture 21 until all or a portion of the mixture becomes a dropletat the input aperture 11. The final step is to touch off the drop 21 toa solid wall of microtiter plate's 14 individual well 15. The mixture 21droplet could also touch off into a liquid already present in the well15.

Referring to FIGS. 11-11A, the pipette tip 10 can include a moldedcapillary hole 22 through one wall that can be used during a non-contactdispense routine. In this modification, an external instrument providesan air source that enters the capillary hole 22 and forces the mixture21 out through the input aperture 11 into the microtiter plate 14. Themolded capillary hole 22 could also be used to meter a specific volumeof source liquid similar to a molded pocket.

Referring to FIGS. 12-12A, the pipette tip 10 can include a protrusionwith capillary like geometry or other modifications of the internalmolded feature 23 for capturing and retaining the source liquid 17.

Referring to FIGS. 13-13A, the pipette tip 10 includes a feature 24 thatprotrudes towards the center of the tip. The feature 24 can include verysoft edges 25 so as to not trap any liquid in small geometric spaces.The feature includes the metering pocket 26 (or pockets) that capturethe source liquid (not shown).

Referring to FIGS. 14-14A, a tube 27 is shown to include multiplepockets. For a clear visual in the drawing, the tube 27 is cut along itscenterline to expose the internal pocket 28 and 29. The closed slotpocket 28 captures and retains source liquid 28 a in the same manner asopen slot pocket 29 captures and retains source liquid 29 a. The sourceliquid could flow in the direction of arrow 30, and return in theopposite direction of arrow 31, leaving a precise amount of sourceliquid 28 a and 29 a in both pocket 28 and pocket 29 respectively. Insome embodiments, the source liquid may be a finite slug and flow onlyin direction of arrow 30, leaving behind a precise amount of sourceliquid 28 a and 29 a in both pocket 28 and pocket 29 respectively.

Referring to FIGS. 15-15A, a chip 32 is shown to include multiplepockets. Chip 32 is a laminated plate that defines multiple capillarychannels to move liquid. Once on the chip, a source liquid sample ismanipulated through the channels of the chip to perform the stepsrequired for mixing, incubation, reaction, separation, and detection.Movement through the channels is controlled using a combination ofpressure and/or voltage. For a clear visual in the drawing, the chip 32is cut along its centerline to expose the internal pocket 34 and 35. Thecapillary channel 33 is connected to an input orifice 36. A pipettingdevice (not shown) containing the source liquid (not shown) connects tothe input orifice 36. The pipetting device moves the source liquid pastthe internal pocket 34 and 35, and then retracts the liquid back out ofthe input orifice 36. The internal pockets 34 and 35 now contain aprecise amount of source liquid (not shown). The pipetting devicereattaches to the chip 32 input orifice 36 and deposits a slug ofdiluent (not shown). The pipetting device moves the diluent back andforth past the pockets 34 and 35 thereby mixing the source liquid andthe diluent. When the pipetting device disconnects from the inputorifice 36, a precise mixture is left in the capillary channel 33.

In FIG. 16, a plate 37 is shown that contains multiple pockets 38. Adevice containing source liquid can drag the source liquid past thepockets 38 and deposit a fixed amount of source liquid.

Referring to FIGS. 17-17A, pipette tip 10 a includes a continuous radialledge 42 that acts as a capillary retention feature. A predetermined,metered dose of the sample liquid 43 is captured and retained bycapillary force on the ledge. In the pipette tip 10 b of FIGS. 18 and18A, the metered dose of the sample liquid is captured and retained bycapillary force in a series of discrete ledge sections 44.

Devices according to the invention can be designed for compatibilitywith various liquids, including aqueous buffers, organic solvents, e.g.,dimethylsulfoxide (DMSO), acids, bases, proteins, oligonucleitides andreagents. Compatibility is achieved by selection of suitable materialsfor fabrication of components that contact the liquid. Exemplarymaterials for fabrication of components are stainless steel, nylon,polyethylene, polypropylene, EPD rubber, silicone rubber andpolytetrafluoroethylene (PTFE; Teflon®). Suitable materials andfabrication of components is within ordinary skill in the art.

A number of embodiments of the invention have been described.Nevertheless, it will be understood that various modifications may bemade without departing from the spirit and scope of the invention. Forexample, the internal pocket could be no more than a surface texture orchemical or biological adherent, enabling a small amount of sourceliquid to adhere where the texture or adherent is present, including anysmall feature, additional part or surface enhancement such as finishroughness, chemistry or biology, (internal or external) that can trapand retain liquid due to capillary force, surface energy, gravity,chemistry bonding or biological bonding (or a combination of all).Accordingly, other embodiments are within the scope of the followingclaims.

1. A pipette comprising: an elongated body having an outer surface andan interior wall, a portion of the interior wall defining an internalcavity open at a lower end of the body; the body defining an opening inan upper portion of the body, through which air can be drawn from thecavity to draw liquids into the cavity through the lower end of thebody; wherein the portion of the interior wall defining the internalcavity also defines a pocket open to the internal cavity, the pocketradially extending into the portion of interior wall defining theinternal cavity, the pocket sized and configured to collect andreleasably retain a metered dose representative of a liquid drawn intothe cavity as the cavity is otherwise evacuated.
 2. The pipetteaccording to claim 1 wherein the body is formed from a synthetic resin.3. The pipette according to claim 1 wherein the body further defines acapillary hole extending from the outer surface to the internal cavity.4. The pipette according to claim 1 wherein the pocket is sized andconfigured to collect a metered dose of sample liquid between about 1nanoliter and about 10 microliters in volume.
 5. The pipette accordingto claim 4 wherein the pocket is sized and configured to collect ametered dose of sample liquid between about 5 nanoliters and about 10microliters in volume.
 6. The pipette according to claim 1 wherein thepocket is disposed in a portion of the internal cavity wider than thecavity at the open end of the body.
 7. The pipette according to claim 1wherein the pocket comprises an upwardly extending notch defined in theinterior wall of the body.
 8. The pipette according to claim 1 whereinthe surface of the pipette defining the lower extent of the pocket issubstantially perpendicular to a longitudinal axis of the body.
 9. Thepipette according to claim 1 wherein the pocket is elongated andparallel to a longitudinal axis of the body.
 10. The pipette accordingto claim 9 wherein the pocket has a length of between about 0.01 andabout 1 inch (0.25 and 25 millimeters), as measured parallel to thelongitudinal axis of the pipette.
 11. The pipette according to claim 9wherein the pocket has a width of between about 0.001 and about 0.04inch (0.025 and 1.02 millimeters).
 12. The pipette according to claim 1wherein the pocket has a depth of between about 0.001 and about 0.100inch (0.025 and 2.54 millimeters), measured along a radial lineextending from the longitudinal axis of the pipette.
 13. The pipetteaccording to claim 1 wherein the body defines a plurality of saidpockets spaced apart from one another.
 14. The pipette according toclaim 1 wherein the pocket is defined in a protrusion extending into theinternal cavity.
 15. The pipette according to claim 1 wherein the pocketis spaced apart from an upper end of the interior wall and is spacedapart from a lower end of the interior wall.
 16. The pipette accordingto claim 1 wherein the outer surface and the interior wall of theelongated body are substantially parallel such that the radial extensionof the pocket into the interior wall of the elongated body results in aportion of the elongated body which is thinner than adjacent portions ofthe elongated body.